Project 1 proposes to obtain scientific data to develop strategies that will prevent or reduce transfusion-related acute lung injury (TRALI), the leading reported cause of transfusion-associated mortality. To achieve this goal, we aim to determine the incidence and mechanisms for the syndrome. The incidence of TRALI is underestimated due to lack of a standard definition and lack of an effective surveillance system of large number of transfusions. Our preliminary data indicate the incidence is as high as 1:500 transfusions in highrisk patients. Using the new NHLBI Working Group definition, we will determine the actual incidence of clinical TRALI by a novel surveillance system of almost one million transfusions at two university hospitals. The surveillance system will capture all cases. The mechanisms of TRALI are unclear because previous case series did not include appropriate controls. The proposed large, prospective study will enroll concurrent control patients who were transfused but did not develop TRALI. The association of clinical factors will be tested in TRALI cases and controls. We will determine whether patient conditions such as surgery or inflammation predispose patients to developing TRALI. We will correlate the transfusion of anti-HLA, antineutrophil and proinflammatory agents in donor blood products with the development of TRALI. We will also determine if there is a correlation between the titer and specificities of anti-HLA and neutrophil antibodies and the development of TRALI. We will determine whether acute neutropenia is pathognomic of antibody-mediated TRALI. The presence of genetic predispositions in TRALI patients will be identified. We will also determine whether leukoreduction removes any risk associated with transfusion of older cellular blood products, by abrogation of cytokines and neutrophil priming activity. Thus, through a large prospective case-control study, we will be able to determine the mechanisms of TRALI. Once this study clarifies the incidence and mechanisms, rational strategies can be developed to limit this potentially life-threatening sydrome.